Background

MAP2K1 mutations, otherwise known as MEK mutations, are rare oncogenic alterations that have been implicated in MAPK pathway activation. The impact of MAP2K1 mutations in colorectal cancer on EGFR antibody response has not been characterized.

Patients and Methods

Antitumor activity was assessed in mouse xenograft models with SW48 cell lines harboring MAP2K1 mutation, and protein expression of the RAS signaling pathway was studied by Western blot analysis. We retrospectively identified patients with MAP2K1-mutated metastatic colorectal cancer patients treated at City of Hope Comprehensive Cancer Center between 2015 and 2020 using next-generation sequencing. Patients’ tumor characteristics, treatment response, and outcome are described. Additional patients with the MAP2K1 mutation were identified from The Cancer Genome Atlas and Memorial Sloan Kettering Cancer Center oncogenomic databases.

Results

Antitumor activity in mouse xenograft models demonstrated efficacy with combination therapy with EGFR and MEK inhibition with either BRAF or ERK inhibitors. Five patients treated at City of Hope between 2015 and 2020 harbored a MAP2K1 mutation at a frequency of 1%. APC and TP53 were common coalterations. All disease was RAS and BRAF wild type, except 1 case that harbored a concurrent KRAS mutation. Four RAS/BRAF wild-type MAP2K1-mutated patients was treated with anti-EGFR, anti-EGFR + MEK and BRAF inhibitors, and anti-EGFR + ERK inhibitors. All 4 patients experienced disease progression.

Conclusion

MAP2K1 mutation in colorectal cancer is associated with poor response to EGFR inhibition. EGFR inhibition with or without MEK, BRAF, or ERK inhibitors did not result in any clinical benefit in our limited experience.

中文翻译：

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晚期结直肠癌中的 MAP2K1 突变预测对抗 EGFR 治疗和 MAPK 通路的垂直靶向反应不佳

背景

MAP2K1突变，也称为MEK突变，是与MAPK通路激活有关的罕见致癌改变。的影响MAP2K1突变在结肠直肠癌上EGFR的抗体应答没有被表征。

患者和方法

在具有MAP2K1突变的SW48 细胞系的小鼠异种移植模型中评估抗肿瘤活性，并通过蛋白质印迹分析研究RAS信号通路的蛋白质表达。我们使用新一代测序技术回顾性地确定了2015 年至 2020 年在希望之城综合癌症中心接受治疗的MAP2K1突变转移性结直肠癌患者。描述了患者的肿瘤特征、治疗反应和结果。从癌症基因组图谱和纪念斯隆凯特琳癌症中心肿瘤基因组数据库中确定了其他具有MAP2K1突变的患者。

结果

在小鼠异种移植模型中的抗肿瘤活性证明了与 EGFR 和MEK抑制以及BRAF或ERK抑制剂联合治疗的疗效。2015 年至 2020 年间在希望之城接受治疗的五名患者携带 MAP2K1突变，其频率为 1%。APC和TP53是常见的合并。除 1 例同时存在KRAS突变外，所有疾病均为RAS和BRAF野生型。四名RAS/BRAF野生型MAP2K1突变患者接受抗EGFR、抗EGFR+ MEK和BRAF治疗抑制剂和抗 EGFR + ERK抑制剂。所有 4 名患者都经历了疾病进展。

结论

结直肠癌中的MAP2K1突变与对 EGFR 抑制的不良反应有关。在我们有限的经验中，使用或不使用MEK、BRAF或ERK抑制剂的EGFR 抑制没有导致任何临床益处。